
`
`
`
`
`
`
`--------------WARNINGS AND PRECAUTIONS--------------
`
`Potential for sulfonamide hypersensitivity reactions
`
`because of the brinzolamide tartrate component (5.1)
`Potential for corneal endothelium cell loss (5.2)
`Severe renal impairment may limit the metabolism of the
`
`brinzolamide tartrate component (5.3)
`
`---------------------ADVERSE REACTIONS---------------------
`
`Most common adverse reactions occurring in approximately 3
`to 5% of patients included blurred vision, eye irritation,
`
`
`dysgeusia (bad taste), dry mouth, eye allergy. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`Alcon Laboratories, Inc. at 1-800-757-9195 or FDA at
`
`
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`---------------------DRUG INTERACTIONS---------------------
`
` Oral Carbonic Anhydrase Inhibitors (7.1)
`
`
` High-dose Salicylate Therapy (7.2)
`
`CNS Depressants (7.3)
`
`
` Antihypertensives/Cardiac Glycosides (7.4)
`
`Tricyclic Antidepressants (7.5)
`
`
` Monoamine Oxidase Inhibitors (7.6)
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed
`to use SIMBRINZA™ safely and effectively. See full
`
`prescribing information for SIMBRINZA™
`
`SIMBRINZA™ (brinzolamide/brimonidine tartrate
`ophthalmic suspension) 1%/0.2%
`
`Initial U.S. Approval: 2013
`
`-------------------INDICATIONS AND USAGE-----------------
`
`SIMBRINZA™ is a fixed combination of a carbonic
`anhydrase inhibitor and an alpha 2 adrenergic receptor agonist
`indicated for the reduction of elevated intraocular pressure in
`
`patients with open-angle glaucoma or ocular hypertension. (1)
`
`
`
`--------------DOSAGE AND ADMINISTRATION-------------
`
`Shake well before use. Instill one drop in the affected eye(s)
`three times daily. If more than one topical ophthalmic drug is
`
`being used, the drugs should be administered at least five (5)
`
`minutes apart. (2)
`
`-------------DOSAGE FORMS AND STRENGTHS------------
`Suspension containing 10 mg/mL brinzolamide and 2 mg/mL
`
`brimonidine tartrate. (3)
`
`---------------------CONTRAINDICATIONS---------------------
`
` Hypersensitivity to any component of this product. (4.1)
`
` Neonates and infants (under the age of 2 years). (4.2)
`
`Revised: 04/2013
`
`
`
`_________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`4.1
` Hypersensitivity
`4.2 Neonates and Infants (under the age of 2 years)
`
`5 WARNINGS AND PRECAUTIONS
`Sulfonamide Hypersensitivity Reactions
`5.1
`
`
`5.2 Corneal Endothelium
`
`
`5.3
`Severe Renal Impairment
`
`
`
`5.4 Acute Angle-Closure Glaucoma
`
`
`5.5 Contact Lens Wear
`
`
`5.6
`Severe Cardiovascular Disease
`Severe Hepatic Impairment
`5.7
`
`
`5.8
`Potentiation of Vascular Insufficiency
`
`5.9 Contamination of Topical Ophthalmic Products
`
`
`
`After Use
`ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`6.2 Postmarketing Experience
`
`DRUG INTERACTIONS
`
`7.1 Oral Carbonic Anhydrase Inhibitors
`
`7.2 High Dose Salicylate Therapy
`
`7.3 CNS Depressants
`7.4 Antihypertensives/Cardiac Glycosides
`7.5 Tricyclic Antidepressants
`7.6 Monoamine Oxidase Inhibitors
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`
`
`13
`
` Pediatric Use
`8.4
`8.5 Geriatric Use
`10 OVERDOSAGE
`11
`DESCRIPTION
`12
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
` Pharmacokinetics
`12.3
`
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`Fertility
`CLINICAL STUDIES
`14
`16 HOW SUPPIED/STORAGE AND HANDLING
`
`17
`PATIENT COUNSELING INFORMATION
`
`17.1 Sulfonamide Reactions
`17.2 Temporary Blurred Vision
`
`17.3 Effect on Ability to Drive and Use Machinery
`
`17.4 Avoiding Contamination of the Product
`
`
`
`17.5 Intercurrent Ocular Conditions
`
`
`17.6 Concomitant Topical Ocular Therapy
`
`
`17.7 Contact Lens Wear
`
`
`
`*Sections or subsections omitted from the full prescribing
`
`information are not listed.
`
`
`
`6
`
`7
`
`8
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 1 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed
`combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist
`indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle
`glaucoma or ocular hypertension.
`
`DOSAGE AND ADMINISTRATION
`2
`The recommended dose is one drop of SIMBRINZA™ in the affected eye(s) three times daily.
`Shake well before use. SIMBRINZA™ ophthalmic suspension may be used concomitantly with
`other topical ophthalmic drug products to lower intraocular pressure. If more than one topical
`
`ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Suspension containing 10 mg/mL brinzolamide and 2 mg/mL brimonidine tartrate.
`
`CONTRAINDICATIONS
`4
`4.1 Hypersensitivity
`SIMBRINZA™ is contraindicated in patients who are hypersensitive to any component of this
`product.
`
`
`4.2
`Neonates and Infants (under the age of 2 years)
`
`SIMBRINZA™ is contraindicated in neonates and infants (under the age of 2 years) [see Use in
`Specific Populations (8.4)].
`
`WARNINGS AND PRECAUTIONS
`5
`Sulfonamide Hypersensitivity Reactions
`5.1
`SIMBRINZA™ contains brinzolamide, a sulfonamide, and although administered topically is
`absorbed systemically. Therefore, the same types of adverse reactions that are attributable to
`sulfonamides may occur with topical administration of SIMBRINZA™. Fatalities have occurred
`due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal
`necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood
`dyscrasias. Sensitization may recur when a sulfonamide is re-administered irrespective of the
`route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the
`use of this preparation [see Patient Counseling Information (17.1)].
`
`Corneal Endothelium
`5.2
`Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma
`
`membranes of the corneal endothelium. There is an increased potential for developing corneal
`edema in patients with low endothelial cell counts. Caution should be used when prescribing
`SIMBRINZA™ to this group of patients.
`
`
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 2 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Severe Renal Impairment
`5.3
`SIMBRINZA™ has not been specifically studied in patients with severe renal impairment (CrCl
`< 30 mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney,
`SIMBRINZA™ is not recommended in such patients.
`
`Acute Angle-Closure Glaucoma
`5.4
`The management of patients with acute angle-closure glaucoma requires therapeutic
`interventions in addition to ocular hypotensive agents. SIMBRINZA™ has not been studied in
`patients with acute angle-closure glaucoma.
`
`Contact Lens Wear
`5.5
`The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact
`
`lenses. Contact lenses should be removed during instillation of SIMBRINZA™ but may be
`reinserted 15 minutes after instillation [see Patient Counseling Information (17.7)].
`
`Severe Cardiovascular Disease
`5.6
`Brimonidine tartrate, a component of SIMBRINZATM, has a less than 5% mean decrease in
`blood pressure 2 hours after dosing in clinical studies; caution should be exercised in treating
`patients with severe cardiovascular disease.
`
`Severe Hepatic Impairment
`5.7
`Because brimonidine tartrate, a component of SIMBRINZA™, has not been studied in patients
`with hepatic impairment, caution should be exercised in such patients.
`
`Potentiation of Vascular Insufficiency
`5.8
`Brimonidine tartrate, a component of SIMBRINZATM, may potentiate syndromes associated with
`vascular insufficiency. SIMBRINZA™ should be used with caution in patients with depression,
`cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or
`thromboangitis obliterans.
`
` Contamination of Topical Ophthalmic Products After Use
` 5.9
`
`
`There have been reports of bacterial keratitis associated with the use of multiple-dose containers
`of topical ophthalmic products. These containers have been inadvertently contaminated by
`patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular
`
`epithelial surface [see Patient Counseling Information (17.4)].
`
`ADVERSE REACTIONS
`6
`Clinical Studies Experience
`6.1
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical
`studies of another drug and may not reflect the rates observed in practice.
`
`SIMBRINZA™ In two clinical trials of 3 months duration 435 patients were treated with
`SIMBRINZA™, and 915 were treated with the two individual components. The most frequently
`reported adverse reactions in patients treated with SIMBRINZA™ occurring in approximately 3
`to 5% of patients in descending order of incidence were blurred vision, eye irritation, dysgeusia
`
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 3 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`(bad taste), dry mouth, and eye allergy. Rates of adverse reactions reported with the individual
`components were comparable. Treatment discontinuation, mainly due to adverse reactions, was
`
`reported in 11% of SIMBRINZA™ patients.
`
`Other adverse reactions that have been reported with the individual components during clinical
`trials are listed below.
`
`Brinzolamide 1%
`
`In clinical studies of brinzolamide ophthalmic suspension 1%, the most frequently reported
`adverse reactions reported in 5 to 10% of patients were blurred vision and bitter, sour or unusual
`taste. Adverse reactions occurring in 1 to 5% of patients were blepharitis, dermatitis, dry eye,
`foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular
`keratitis, ocular pain, ocular pruritus and rhinitis.
`
`The following adverse reactions were reported at an incidence below 1%: allergic reactions,
`alopecia, chest pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia,
`eye fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or
`sticky sensation, nausea, pharyngitis, tearing and urticaria.
`
`Brimonidine Tartrate 0.2%
`
`In clinical studies of brimonidine tartrate 0.2%, adverse reactions occurring in approximately 10
`to 30% of the subjects, in descending order of incidence, included oral dryness, ocular
`hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness,
`conjunctival follicles, ocular allergic reactions, and ocular pruritus.
`
`Reactions occurring in approximately 3 to 9% of the subjects, in descending order included
`corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing,
`upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular
`irritation, gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and
`muscular pain.
`
`The following adverse reactions were reported in less than 3% of the patients: lid crusting,
`conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression,
`hypertension, anxiety, palpitations/arrhythmias, nasal dryness and syncope.
`
`
`Postmarketing Experience
`6.2
`
`The following reactions have been identified during postmarketing use of brimonidine tartrate
`ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population
`of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen
`for inclusion due to either their seriousness, frequency of reporting, possible causal connection to
`brimonidine tartrate ophthalmic solutions, or a combination of these factors, include:
`bradycardia, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions
`(including erythema, eyelid pruritus, rash, and vasodilation), and tachycardia.
`
`
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 4 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory
`depression, and somnolence have been reported in infants receiving brimonidine tartrate
`ophthalmic solutions [see Contraindications (4.3)].
`
`
`DRUG INTERACTIONS
`7
`7.1 Oral Carbonic Anhydrase Inhibitors
`There is a potential for an additive effect on the known systemic effects of carbonic anhydrase
`inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic
`suspension 1%, a component of SIMBRINZA™. The concomitant administration of
`SIMBRINZA™ and oral carbonic anhydrase inhibitors is not recommended.
`
`7.2 High-Dose Salicylate Therapy
`Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These
`alterations were not reported in the clinical trials with brinzolamide ophthalmic suspension 1%.
`However, in patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base
`alterations have occurred with high-dose salicylate therapy. Therefore, the potential for such
`drug interactions should be considered in patients receiving SIMBRINZA™.
`
`CNS Depressants
`7.3
`Although specific drug interaction studies have not been conducted with SIMBRINZA™, the
`possibility of an additive or potentiating effect with CNS depressants (alcohol, opiates,
`barbiturates, sedatives, or anesthetics) should be considered.
`
`Antihypertensives/Cardiac Glycosides
`7.4
`Because brimonidine tartrate, a component of SIMBRINZA™, may reduce blood pressure,
`caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA™
`is advised.
`
`Tricyclic Antidepressants
`7.5
`Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic
`clonidine. It is not known whether the concurrent use of these agents with SIMBRINZA™ in
`humans can lead to resulting interference with the IOP lowering effect. Caution is advised in
`patients taking tricyclic antidepressants which can affect the metabolism and uptake of
`circulating amines.
`
`
`7.6 Monoamine Oxidase Inhibitors
`
`Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of
`brimonidine tartrate and potentially result in an increased systemic side-effect such as
`
`hypotension. Caution is advised in patients taking MAO inhibitors which can affect the
`metabolism and uptake of circulating amines.
`
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Pregnancy Category C: Developmental toxicity studies with brinzolamide in rabbits at oral
`doses of 1, 3, and 6 mg/kg/day (20, 60, and 120 times the recommended human ophthalmic dose)
`
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 5 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal
`variations, such as accessory skull bones, which was only slightly higher than the historic value
`at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving
`oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during
`gestation were proportional to the reduced maternal weight gain, with no statistically significant
`effects on organ or tissue development. Increases in unossified sternebrae, reduced ossification
`of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically
`significant. No treatment-related malformations were seen. Following oral administration of 14C­
`brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in
`the fetal tissues and blood.
`
`Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg
`revealed no evidence of harm to the fetus. Dosing at this level resulted in a plasma drug
`concentration approximately 100 times higher than that seen in humans at the recommended
`human ophthalmic dose. In animal studies, brimonidine crossed the placenta and entered into the
`fetal circulation to a limited extent.
`
`
`
`There are no adequate and well-controlled studies in pregnant women. SIMBRINZA™ should
`be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Nursing Mothers
`8.3
`In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral
`dose of 15 mg/kg/day (150 times the recommended human ophthalmic dose) were observed
`during lactation. No other effects were observed. However, following oral administration of 14C­
`brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in
`
` the blood and plasma. In animal studies, brimonidine was excreted in breast milk.
`
`It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk
`following topical ocular administration. Because many drugs are excreted in human milk and
`because of the potential for serious adverse reactions in nursing infants from SIMBRINZA™
`(brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2%, a decision should be made
`whether to discontinue nursing or to discontinue the drug, taking into account the importance of
`the drug to the mother.
`
`Pediatric Use
`8.4
`The individual component, brinzolamide, has been studied in pediatric glaucoma patients 4
`weeks to 5 years of age. The individual component, brimonidine tartrate, has been studied in
`pediatric patients 2 to 7 years old. Somnolence (50-83%) and decreased alertness was seen in
`patients 2 to 6 years old. SIMBRINZA™ is contraindicated in children under the age of 2 years
`[see Contraindications (4.3)].
`
`8.5 Geriatric Use
`No overall differences in safety or effectiveness have been observed between elderly and adult
`patients.
`
`
`
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 6 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`OVERDOSAGE
`10
`Although no human data are available, electrolyte imbalance, development of an acidotic state,
`and possible nervous system effects may occur following an oral overdose of brinzolamide.
`Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.
`
`Very limited information exists on accidental ingestion of brimonidine in adults; the only
`adverse event reported to date has been hypotension. Symptoms of brimonidine overdose have
`been reported in neonates, infants, and children receiving brimonidine as part of medical
`treatment of congenital glaucoma or by accidental oral ingestion. Treatment of an oral overdose
`includes supportive and symptomatic therapy; a patent airway should be maintained.
`
`
`DESCRIPTION
`11
`SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed
`combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist.
`
`Brinzolamide is described chemically as: (R)-(+)-4-Ethylamino-2-(3-methoxypropyl)-3,4­
`dihydro-2H-thieno [3,2-e]-1,2-thiazine-6-sulfonamide-1,1- dioxide. Its empirical formula is
`C12H21N3O5S3, and its structural formula is:
`
`
`NHCH2CH3
`
`H2N
`
`O
`
`S
`
`O
`
`S
`
`N
`
`S
`
`O
`
`O
`O
`
`Brinzolamide has a molecular weight of 383.5. It is a white powder, which is insoluble in water,
`very soluble in methanol and soluble in ethanol.
`
`
`Brimonidine tartrate is described chemically as: 5-bromo-6-(2-imidazolidinylideneamino)
`quinoxaline L-tartrate. Its empirical formula of C11H10BrN5 – C4H6O6 and its structural formula
`is:
`O H
`
`OH
`
`Br
`
`H
`
`N
`
`N
`
`OH
`
`N
`
`H
`
`H
`
`OH O
`
`OH
`
`
`
`N
`
`N
`
`
`
`
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 7 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Brimonidine tartrate has a molecular weight of 442.2. It is a white to yellow powder that is
`soluble in water (34 mg/mL) at pH 6.5.
`
`SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is supplied
`as a sterile, aqueous suspension which has been formulated to be readily suspended following
`shaking. It has a pH of approximately 6.5 and an osmolality of approximately 270 mOsm/kg.
`
`Each mL of SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension)
`1%/0.2% contains: Active ingredients: brinzolamide 10 mg, brimonidine tartrate 2 mg
`(equivalent to 1.32 mg as brimonidine free base); Preservative: benzalkonium chloride 0.03 mg;
`Inactive ingredients: propylene glycol, carbomer 974P, boric acid, mannitol, sodium chloride,
`tyloxapol and purified water. Hydrochloric acid and/or sodium hydroxide may be added to adjust
`pH.
`
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`SIMBRINZA™ is comprised of two components: brinzolamide (carbonic anhydrase inhibitor)
`and brimonidine tartrate (alpha 2 adrenergic receptor agonist). Each of these two components
`decreases elevated intraocular pressure. Elevated intraocular pressure is a major risk factor in
`the pathogenesis of optic nerve damage and glaucomatous visual field loss. The higher the level
`of intraocular pressure, the greater the likelihood of glaucomatous field loss and optic nerve
`damage.
`
`Brinzolamide inhibits carbonic anhydrase in the ciliary processes of the eye to decrease aqueous
`humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent
`reduction in sodium and fluid transport. Brinzolamide has a peak ocular hypotensive effect
`occurring at 2 to 3 hours post-dosing. Fluorophotometric studies in animals and humans suggest
`that brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production
`and increasing uveoscleral outflow. Brimonidine tartrate has a peak ocular hypotensive effect
`occurring at two hours post-dosing. The result is a reduction in intraocular pressure (IOP).
`
`12.3 Pharmacokinetics
`Following topical ocular administration, brinzolamide is absorbed into the systemic circulation.
`Due to its affinity for CA-II, brinzolamide distributes extensively into the RBCs and exhibits a
`long half-life in whole blood (approximately 111 days). In humans, the metabolite N-desethyl
`brinzolamide is formed, which also binds to CA and accumulates in RBCs. This metabolite binds
`mainly to CA-I in the presence of brinzolamide. In plasma, both parent brinzolamide and N­
`desethyl brinzolamide concentrations are <10 ng/mL. Binding to plasma proteins is
`approximately 60%. Brinzolamide is eliminated predominantly in the urine as unchanged drug.
`N-Desethyl brinzolamide is also found in the urine along with lower concentrations of the N­
`desmethoxypropyl and O-desmethyl metabolites.
`
`After ocular administration of a 0.2% solution of brimonidine tartrate, plasma concentrations
`peaked within 1 to 4 hours and declined with a systemic half-life of approximately 3 hours. In
`humans, systemic metabolism of brimonidine is extensive. It is metabolized primarily by the
`
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 8 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`liver. Urinary excretion is the major route of elimination of the drug and its metabolites.
`Approximately 87% of an orally-administered radioactive dose was eliminated within 120 hours,
`with 74% found in the urine.
`
`
`In humans, a study was conducted to evaluate the pharmacokinetics of the fixed combination of
`brinzolamide / brimonidine tartrate 1%/ 0.2% ophthalmic suspension. Healthy volunteers were
`randomly assigned to receive twice or three times a day either the fixed combination, or either of
`its individual components, brinzolamide or brimonidine. Subjects who were assigned to the
`brinzolamide alone or combination arms were administered oral brinzolamide capsules for two
`weeks prior to beginning dosing with the topical ocular suspension. The results demonstrate that
`the systemic plasma exposure (AUC and Cmax) to brinzolamide and brimonidine in humans is
`similar after dosing with the fixed combination to that observed following dosing with the
`individual components.
`
`
`NONCLINICAL TOXICOLOGY
`13
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`The following tests for mutagenic potential of brinzolamide were negative: (1) in vivo mouse
`micronucleus assay; (2) in vivo sister chromatid exchange assay; and (3) Ames E. coli test. The
`in vitro mouse lymphoma forward mutation assay was negative in the absence of activation, but
`positive in the presence of microsomal activation. In this assay, there was no consistent dose-
`response relationship to the increased mutation frequency and cytotoxicity likely contributed to
`the high mutation frequency. Carbonic anhydrase inhibitors, as a class, are not mutagenic and the
`weight of evidence supports that brinzolamide is consistent with the class. In reproduction
`studies of brinzolamide in rats, there were no adverse effects on the fertility or reproductive
`capacity of males or females at doses up to 18 mg/kg/day (180 times the recommended human
`ophthalmic dose).
`
`Brimonidine tartrate was not carcinogenic in either a 21-month mouse or 24-month rat study. In
`these studies, dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice
`and 1 mg/kg/day in rats resulted in plasma drug concentrations 80 and 120 times higher than the
`human plasma drug level at the recommended clinical dose, respectively. Brimonidine tartrate
`was not mutagenic or cytogenic in a series of in vitro and in vivo studies including the Ames test,
`chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, a host-mediated assay
`and cytogenic studies in mice, and a dominant lethal assay. In reproductive studies performed in
`rats with oral doses of 0.66 mg brimonidine base/kg (approximately 100 times the plasma drug
`concentration level seen in humans following multiple ophthalmic doses), fertility was not
`impaired.
`
`
`14
`
`Two clinical trials of 3 months duration were conducted in patients with open-angle glaucoma or
`ocular hypertension to compare the IOP-lowering effect of SIMBRINZA™
`(brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% dosed three times daily
`
`CLINICAL STUDIES
`
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 9 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`(TID) to individually administered 1% brinzolamide three times daily and 0.2% brimonidine
`tartrate three times daily. Mean IOP values at baseline are presented in Table 1.
`
`
`
`
`Table 1. Mean (SD) IOP values at baseline
`SIMBRINZA™
`Brinzolamide
`
`
`The IOP-lowering effect of SIMBRINZA™ was 1 to 3 mmHg greater than monotherapy with
`either 1% brinzolamide or 0.2% brimonidine tartrate throughout the duration of the trials. Least
`Square Mean IOP (mmHg) and the results at Week 2, Week 6 and Month 3 for each study are
`provided in Table 2.
`
`
`
`(n=209)
`26.9 (2.63)
`25.3 (2.76)
`23.7 (2.98)
`
`23.2 (3.08)
`(n=218)
`
` 27.2 (2.75)
`25.8 (3.09)
`24.4 (3.67)
`24.1 (3.71)
`
`
`(n=224)
`27.1 (2.64)
`25.4 (2.74)
`23.8 (3.24)
`23.6 (3.39)
`(n=229)
`
` 27.2 (2.72)
`26.0 (3.20)
`24.4 (3.58)
`24.2 (3.86)
`
`
`Brimonidine
`
`
`(n=216)
` 27.0 (2.56)
`
`25.4 (2.78)
`24.0 (3.27)
`23.7 (3.30)
`(n=232)
`
` 27.3 (2.73)
`25.8 (3.02)
`24.0 (3.39)
`23.7 (3.58)
`
`
`
`
`
`Study 1
`
`
`
`
`
`Study 2
`
`
`
`
`
`
`8 AM
`
`
` 10 AM
`
`
`
`3 PM
`
`
`5 PM
`
`
`
`8 AM
`
` 10 AM
`
`
`
`3 PM
`
`
`5 PM
`
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 10 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Table 2 Mean IOP (mmHg) by Treatment Group and Treatment Difference in Mean IOP
`
`
`SIMBRINZA™
`Brimonidine
`Brinzolamide
`
`
`
`(N=209)
`(N=216)
`(N=224)
`Study 1
`
`Mean
`Mean Difference (95% CI)** Mean
`
`Difference (95% CI)**
`
`
`Week 2
`
`
`
`-2.0 (-2.7, -1.3)
`20.4
`8 AM
` 10 AM
`
`17.1
`-2.3 (-3.0, -1.6)
`
` 3 PM
`18.4
`-2.2 (-2.9, -1.5)
`
` 5 PM
`16.6
`-1.9 (-2.6, -1.2)
`
`
`Week 6
`
`
`
`-2.3 (-3.0, -1.6)
`20.4
`8 AM
` 10 AM
`
`17.5
`-2.0 (-2.7, -1.3)
`
` 3 PM
`18.9
`-2.1 (-2.8, -1.4)
`
` 5 PM
`17.0
`-1.5 (-2.2, -0.8)
`
`
`
` Month 3
`
`
`
`-2.8 (-3.5, -2.1)
`20.5
`8 AM
` 10 AM
`
`17.2
`-2.5 (-3.2, -1.8)
`
` 3 PM
`18.7
`-2.6 (-3.3, -1.9)
`
` 5 PM
`17.0
`-1.8 (-2.5, -1.1)
`
`
`
`
` (N=218)
`Study 2
`
`
`
`Week 2
`
`-2.4 (-3.1, -1.7)
`22.2
`20.5
`8 AM
` 10 AM
`
`20.7
`17.4
`-1.8 (-2.5, -1.2)
`
` 3 PM
`20.5
`18.7
`-2.3 (-3.0, -1.6)
`
` 5 PM
`20.1
`16.5
`-1.8 (-2.4, -1.1)
`
`
`
`Week 6
`
`-2.5 (-3.2, -1.8)
`21.9
`20.7
`8 AM
` 10 AM
`
`20.5
`17.4
`-2.3 (-3.0, -1.6)
`
` 3 PM
`20.2
`19.3
`-1.9 (-2.6, -1.2)
`
` 5 PM
`19.9
`16.9
`
`-1.7 (-2.4, -1.0)
`
`
`
`
` Month 3
`
`
` -1.0 (-1.7, -0.3)
`-2.2 (-2.9, -1.5)
`
`23.2
`22.0
`21.1
`8 AM
`
`
` -2.8 (-3.5, -2.1)
`-1.9 (-2.6, -1.2)
` 10 AM
`
`20.8
`18.0
`19.9
`
`
` -1.2 (-1.9, -0.5)
`-2.0 (-2.7, -1.3)
`
` 3 PM
`20.7
`19.5
`21.5
`
`
` -3.2 (-3.9, -2.5)
`-1.7 (-2.4, -1.0)
`
` 5 PM
`20.4
`17.2
`18.9
`
` *Based on the Intent-to-Treat Population defined as all patients who received study drug and completed at least 1 on-therapy study visit.;
`
` **The estimates are based on least square means derived from a linear mixed model that accounts for correlated IOP measurements within
`
`
`
`
` patient; Treatment difference is SIMBRINZA minus individual component. CI=95% Confidence Interval.
`
`
`
`
`22.4
`19.4
`20.6
`18.4
`
`22.6
`19.5
`21.1
`18.6
`
`23.3
`19.7
`21.3
`18.8
`
`22.8
`19.2
`21.1
`18.3
`
`23.2
`19.7
`21.2
`18.5
`
`(N=229)
`
`
`
` (N=232)
`
`
`
`22.0
`20.5
`20.4
`19.7
`
`21.9
`20.2
`20.2
`19.7
`
`21.6
`20.4
`20.4
`20.0
`
`
`
`
`-1.6 (-2.3, -0.9)
`-3.4 (-4.1, -2.7)
`-1.9 (-2.6, -1.3)
`-3.2 (-3.9, -2.5)
`
`-1.5 (-2.2, -0.8)
`-2.7 (-3.4, -2.0)
`-1.2 (-1.9, -0.5)
`-2.6 (-3.3, -1.9)
`
`-1.1 (-1.8, -0.4)
`-3.2 (-3.9, -2.5)
`-1.8 (-2.5, -1.1)
`-3.0 (-3.7, -2.3)
`
`-1.7 (-2.4, -1.0)
`-3.3 (-4.0, -2.6)
`-1.7 (-2.4, -1.1)
`-3.6 (-4.3, -2.9)
`
`-1.2 (-1.9, -0.5)
`-3.1 (-3.8, -2.4)
`-0.8 (-1.5, -0.2)
`-3.0 (-3.7, -2.3)
`
`
`Figures 1 and 2 present the mean of individual subject IOP changes from baseline at Week 2,
`Week 6, and at Month 3 based on the observed data for the intent-to-treat population.
`
`
`
`
`
`
`Reference ID: 3296143
`
`Eye Therapies Exhibit 2181, 11 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Figure 1. Mean IOP Change from Baseline (Study 1)
`
`
`
`Figure 2. Mean IOP Change from Baseline (Study 2)
`
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is supplied
`in white low density polyethylene (LDPE) DROP-TAINER® bottles with a natural LDPE
`dispensing-tip and white polypropylene cap as follows:
`
`8 mL in a 10 mL bottle NDC 0065-4147-27
`
`Storage and Handling
`Store SIMBRINZA™ at 2 - 25°C (36 - 77°F).
`
`
`
`
`Reference ID: 3296143
`
`
`
`
`
`Eye Therapies Exhibit 2181, 12 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`PATIENT COUNSELING INFORMATION
`17
`17.1 Sulfonamide Reactions
`Advise patients that if serious or unusual ocular or systemic reactions or signs of hypersensitivity
`occur, they should discontinue the use of the product and consult their physician.
`
`17.2 Temporary Blurred Vision
`Vision may be temporarily blurred following dosing with SIMBRINZA™. Care should be
`exercised in operating machinery or driving a motor vehicle.
`
`17.3 Effect on Ability to Drive and Use Machinery
`
`As with other drugs in this class, SIMBRINZA™ may cause fatigue and/or drowsiness in some
`
`patients. Caution patients who engage in hazardous activities of the potential for a decrease in
`mental alertness.
`
`17.4 Avoiding Contamination of the Product
`Instruct patients that ocular solutions, if handled improperly or if the tip of the dispensing
`container contacts the eye or surrounding structures, can become contaminated by common
`bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of
`vision may result from using contaminated solutions [see Warnings and Precautions (5.9)].
`Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do
`not use the product after the expiration date marked on the bottle.
`
`Intercurrent Ocular Conditions
`17.5
`Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g.,
`traum